Inward-rectifying potassium channels (Kir) are playing a number of physiologically important roles (1). Based on their mutual sequence similarity, the Kir family is currently divided into seven subfamilies, Kir1.x–Kir7.x (1–3, 27). Unlike the other members of the Kir family, the members of Kir6.x subfamily, including Kir6.1 and Kir6.2, are unique in that they cannot form functional K+ channels by themselves on the surface of cell membranes and that they require a regulatory SUR subunit) (4–6), which is the receptor for sulfonylurea compounds widely used for the treatment of Type II diabetes mellitus (noninsulin-dependent diabetes mellitus). The sulfonylurea receptor has two isoforms, SUR1 and SUR2 (7), derived from two different genes (7). In addition, there are several splicing variants of SUR2, among which major ones are SUR2A (7) and SUR2B (8). Co-expression of Kir6.2 subunit with SUR1, SUR2A or SUR2B or one of other SUR2 variant subunits produces KATP channel currents with distinct nucleotide and pharmacological sensitivities in heterologous expression systems (4–6). The Kir6.2 subunit and the SUR1 subunit constitute the KATP channel in pancreatic β-cells (9) and in the glucose-responsive neurons (GRNs) in ventromedial hypothalamus (VMH) (10). The Kir6.2 subunit and the SUR2A subunit constitute KATP channels in cardiomyocytes and probably also in skeletal muscle cells (7). The Kir6.1 subunit and the SUR2B subunit constitute KATP channels in non-vascular smooth muscles (8). Studies of Kir6.2 knockout mice have clarified a variety of physiological roles of Kir6.2-containing KATP channels. For example, the Kir6.2/SUR1 channels in pancreatic β-cells are critical in both glucose-induced and sulfonylurea insulin secretion (11), while in VMH, Kir 6.2/SUR1 channels are involved in glucagon secretion during hypoglycemia (10) through autonomic neurons. Studies of SUR1 knockout mice confirm the importance of Kir6.2/SUR1 channels in insulin secretion (12). Kir6.2/SUR2A channels mediate the depression of cardiac excitability and contractility induced by K+ channel openers (KCOs) (13), and contribute in part to ischemic preconditioning (14). In addition, in studies of SUR2 knockout mice, Kir6.2-containing KATP channels in skeletal muscle have been shown to be involved in glucose uptake (15). While Kir6.1 subunits and SUR1 (16, 17), SUR2A (18), or SUR2B (19–21) subunits have been shown to generate K+-channel currents with different electrophysiological and pharmacological properties, the actual combinations of Kir6.1 and SUR subunits naturally occurring in tissues, as well as their physiological roles, have not been determined.
Kir6.1 (its amino acid sequence is set forth as SEQ ID NO:1) shares 63.7% amino acid identity with its isoform Kir6.2. In addition, while inward-rectifier K+ channels generally have the Gly-Tyr-Gly motif in their ion permeable region (H5), both Kir6.1 and Kir6.2 have the Gly-Phe-Gly motif in the region (6). Thus, Kir6.1 and Kir6.2 are structurally very similar. While the electrophysiological and pharmacological properties of Kir6.2-containing K+ channels have been well characterized in reconstituted systems (7–9) and native cells (10, 11, 13), those of Kir6.1-containing K+ channels are not fully understood. Co-expression of Kir6.1 and SUR1 in HEK293 cells produces tolbutamide-sensitive K+ channel currents (16), and co-expression of Kir6.1 and SUR2A in COS7 cells produces currents that are responsive to very high concentrations of UDP (18). Their physiological significance, however, is not known. Co-expression of Kir6.1 and SUR2B, which is a splice variant of SUR2A in HEK293T cells, produces a K+ current which is insensitive to ATP, activated by nucleoside diphosphates such as UDP, and inhibited by sulfonylurea glibenclamide (19). These properties are similar with those of KNDP channels in native vascular smooth muscle (28). The KNDP channel in vascular smooth muscle was originally called the smooth muscle KATP channel as it is closed by glibenclamide (29), a KATP channel blocker, but it has become designated as KNDP channel because of its insensitivity to ATP (28). Since the KNDP channels are opened by K+ channel openers having vasodilating effects, such as cromakalim and pinacidil, the channels are thought to be involved in the vasodilatation response of vascular smooth muscles. However, it is unknown whether Kir6.1 is a component of the KNDP channels in native vascular smooth muscle.
On the other hand, there is a type of human angina pectoris called Prinzmetal angina (also called variant angina or vasospastic angina), which is accompanied by a reversible, tentative of ST elevation during angina attacks in the resting state. Attacks of Prinzmetal angina occurs in the resting state, especially from the night to early morning while one is sleeping. It is characterized by ST segment elevation on electrocardiogram upon attack with a lead which generally should record lowered ST segment in a typical angina pectoris, and it often shows arrhythmia such as ventricular extrasystole, atrioventricular block, ventricular fibrillation, etc. The attack is considered to be caused by sharp decrease of the coronary blood flow due to a spasm of a thick coronary artery.